1. Field of Invention
This invention relates generally to the electrochemical treatment of tissues by applying a voltage across electrodes to cause a current to flow through the tissue. In one embodiment of the invention, the current flow produces an electrochemical reaction yielding multiple reaction products some of which act as cytotoxic agents to destroy cancer cells, the voltage being regulated to optimize the yield of those cytotoxic agents having the greatest efficacy. In another embodiment, fed into the tumor is one or more reagents which when current flows through the tumor react with the material of an electrode to yield a cytotoxic agent. Alternatively, the surface of the electrode can serve as a catalyst for the formation of the cytotoxic agents.
2. Status of Prior Art
Oncology is the branch of medical science dealing with tumors. The prime concern of the present invention is with treatment of tumors and other forms of neoplasm. The distinction between a benign and a malignant tumor is that the latter will invade surrounding tissues and spread or metastasize to other sites, whereas a benign tumor will not spread.
The common practice in the field of oncology to cure or ameliorate a cancerous condition is by appropriate surgery, radiotherapy or chemotherapy, sometimes used singly, but more often in combination.
Radiotherapy which produces its biologic effect on cancerous tissue by ionization is carried out by megavolt energy radiation in the form of X-rays from a linear accelerator or gamma rays from a cobalt 60 source. Radiation is highly penetrating, but in order to reach the region of the tumor being treated, the radiation beam must pass through regions containing healthy tissue and may therefore destroy these as well as the malignant tumor.
Chemotherapy dictates the utmost care in monitoring and controlling the administration of cytotoxic drugs, for the biochemistries of malignant and non-malignant cells are so similar that it is difficult to destroy cancerous cells without concurrently destroying healthy cells. The adverse effects of chemotherapy are notorious.
One of the most potent an widely used substances in the chemotherapy today is cisplatin (Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug, Bernhard Lippert, Ed, Wiley, V C H, Weinheim, 1999). It is a platinum compound, first observed to form by electrochemical reaction in a cell culture by Barnett Rosenberg et al (Inhibition of Cell Division in Escherichia coli by Electrolysis Products from Platinum Electrode, Nature, Vol. 205, pp. 698-9, 1965). This work resulted in discovery of cisplatin as cytotoxic agent, highly effective in cancer treatment. Follow-up work by Rosenberg and co-workers showed that several platinum compounds have antitumor properties (Platinum Compounds: a New Class of Potent Antitumor Agents, Nature, vol. 222, pp. 385-6, 1969). Some other platinum group compounds have also been shown to destroy cancer tissue.
Both cisplatin and other platinum compounds are manufactured synthetically and administered, in most cases, intravenously. The major problem with chemotherapy drugs is a lack of selectivity (both cancerous and normal tissues are affected) and high toxicity for healthy tissue. In the case of cisplatin, there are severe side effects in form of kidney toxicity and nausea and vomiting. The kidney toxicity is currently controlled by hydration and the nausea and vomiting by drugs. Thus the intravenously administered doses currently used are limited by patient's tolerance to the drug rather than being optimized for dose effectiveness in cancer treatment.
In the case of solid tumors, experimental efforts are being made to minimize the side effects through a local delivery either through an injection of the anticancer agent directly to the tumor or through release of various anticancer agents encapsulated in e.g., hydrogels.
It is also known to destroy malignant tumors by elevating the temperature of the tumor to a level at which cancerous cells are destroyed. One method used for this purpose is to focus a beam of microwave energy of the type generated in a microwave oven onto the tumor. But the drawback of this technique is that healthy tissues through which the beam must pass to reach the tumor have a higher moisture content than the interior of the tumor and are therefore more reactive to microwave energy.
The problem with surgery to excise a malignant tumor is that the location of the tumor, as in the case of a tumor in the brain, may be such as to render the tumor inoperable. But even where the tumor is accessible to the surgeon's scalpel, then in order to reach this tumor, one must cut through and damage healthy tissue. Moreover with surgery, one cannot be sure that all malignant cells have been removed, and the residual cells may metastasize.
The primary concern of the present invention is with in situ electrochemical treatment of a malignant tumor, the treatment acting to destroy the tumor with minimal damage to regions surrounding the tumor.
In an existing electrochemical treatment (ECT), electrodes are implanted at spaced positions in or around the malignant tumor to be treated. Applied across these electrodes is a low dc voltage usually having a magnitude of less than 10 volts, causing a current to flow between the electrodes through the tumor. Due to an electrochemical reaction, reaction products are yielded which include cytotoxic agents that act to destroy the tumor.
In the ECT technique disclosed by Li et al., in Bioelectromagnetics 18:2-7 (1997), in an article “Effects of Direct Current on Dog Liver: Possible Mechanisms For Tumor Electrochemical Treatment” two platinum anode and cathode electrodes were inserted in a dog's liver with a 3 cm separation therebetween. Applied across these electrodes was a dc voltage of 8.5 volts, giving rise to an average current through the liver of 30 mA. This was continued for 69 minutes, with a total charge of 124 coulombs. The concentration of selected ions near the anode and cathode were measured. The concentration of Na+ and K+ ions were found to be higher around the cathode, whereas the concentration of C1− ions was higher around the anode. Water content and pH were determined near the anode and cathode, the pH values being 2.1 near the anode and 12.9 near the cathode. The released gases were identified as chlorine at the anode and hydrogen at the cathode. The series of electrochemical reactions which took place during ECT resulted in the rapid and complete destruction of both normal and tumor cells in the liver.
Another example of ECT appears in the article “Electrochemical Treatment of Lung Cancer” by Xin et al. in Bioelectromagnetics 18:8-13 (1997). In this ECT procedure platinum electrodes were inserted transcutaneously into the tumor, the voltage applied thereto being in the 6-8 volt range, the current being in the 40 to 100 mA range, and the electric charge, 100 coulombs per cm of tumor diameter.
According to this article, the clinical results indicate that ECT provides a simple, safe and effective way of treating lung cancers that are surgically inoperable and are not responsive to chemotherapy or radiotherapy.
Also disclosing an ECT technique is the patent to Anderson U.S. Pat. No. 5,360,440 In Situ Apparatus For Generating An Electrical Current in a Biological Environment.”
Electrochemical reactions as a function of pH and electrode potential can be predicted by means of a Pourbaix diagram, as disclosed in the Atlas of Electrochemical Equilibria in Aqueous Solutions—Pergamon Press, 1966—by Pourbaix. Reaction products of electrolysis of water include hydrogen, oxygen, and hydrogen peroxide (H2O2).
In the text Methods in Cell Biology, Vol. 46—Cell Death—published by Academic Press, 1995, it is noted (page 163), that hydrogen peroxide has been reported to be an inducer of cell death in various cell systems. This type of cell death is attributed to the direct cytotoxicity of H2O2 and other oxidant species generated from H2O2.
The present invention also involves an electrochemical technique for cancer treatment in which cisplatin, a highly-effective cytotoxic agents or other cytotoxic agents are produced in situ. Of background interest therefore is the article in the Jul. 5, 1999 issue of The Scientist “From Basic Research to Cancer Drug, The Story of Cisplatin.”